Hit-to-Lead Optimization of Benzoxazepinoindazoles As Human African Trypanosomiasis Therapeutics

Klug, Dana M.; Tschiegg, Laura; Díaz, Rafael Manuel Jiménez; Rojas-Barros, Domingo I.; Pérez-Moreno, Guiomar; Ceballos, Gloria; García-Hernández, Raquel; Martínez-Martínez, María Santos; Manzano, Pilar; Ruiz, Luis Miguel; Caffrey, Conor R.; Gamarro, Francisco; Pacanowska, Dolores González; Ferrins, Lori; Navarro, Miguel; Pollastri, Michael P.

doi:10.1021/acs.jmedchem.9b01506

Cited by 15 publications

(9 citation statements)

References 7 publications

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“…Although the number of HAT patients is decreasing every year, many people living in sub-Saharan Africa are still at risk of infection. In the past few years, a number of publications ,,− indeed specifically focused on antitrypanosomal drug discovery. Compared to these published scaffolds, the pyrazolopyrimidinones (including 30 ) have a relatively low molecular weight, which is for most of the analogs lower than 300 Dalton.…”

Section: Discussionmentioning

confidence: 99%

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy

et al. 2023

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Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei, is one of the neglected tropical diseases with a continuing need for new medication. We here describe the discovery of 5-phenylpyrazolopyrimidinone analogs as a novel series of phenotypic antitrypanosomal agents. The most potent compound, 30 (NPD-2975), has an in vitro IC50 of 70 nM against T. b. brucei with no apparent toxicity against human MRC-5 lung fibroblasts. Showing good physicochemical properties, low toxicity potential, acceptable metabolic stability, and other pharmacokinetic features, 30 was further evaluated in an acute mouse model of T. b. brucei infection. After oral dosing at 50 mg/kg twice per day for five consecutive days, all infected mice were cured. Given its good drug-like properties and high in vivo antitrypanosomal potential, the 5-phenylpyrazolopyrimidinone analog 30 represents a promising lead for future drug development to treat HAT.

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Section: Discussionmentioning

confidence: 99%

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy

et al. 2023

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“…We have phenotypically screened compounds that were originally synthesized for ongoing human African trypanosomiasis and Leishmaniasis neglected tropical disease drug discovery programs ( Diaz et al, 2014 ; Bachovchin et al, 2019 ) that yielded benzoxazepinoindazoles ( Klug et al, 2019 ), pyrazolopyridazines ( Tear et al, 2020 ), substituted azaindoles ( Klug et al, 2021 ), and aminopurines ( Singh et al, 2020 ). The imidazopyridines ( Akao et al, 2021 ) were identified by the Drugs for Neglected Diseases initiative (DND i ) via the Neglected Tropical Disease (NTD) Drug Discovery Booster project ( Drugs for Neglected Diseases Initiative, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

Ferrins,

Buskes,

Kapteyn

et al. 2023

Front. Microbiol.

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Acanthamoeba species, Naegleria fowleri, and Balamuthia mandrillaris are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (>90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.0. Herein, we report the activity of the compounds against the trophozoite stage of each of the three amoebae, ranging from nanomolar to low micromolar potency. The most potent compounds that were identified from this screening effort were: 2d (A. castellanii EC50: 0.92 ± 0.3 μM; and N. fowleri EC50: 0.43 ± 0.13 μM), 1c and 2b (N. fowleri EC50s: <0.63 μM, and 0.3 ± 0.21 μM), and 4b and 7b (B. mandrillaris EC50s: 1.0 ± 0.12 μM, and 1.4 ± 0.17 μM, respectively). With several of these pharmacophores already possessing blood–brain barrier (BBB) permeability properties, or are predicted to penetrate the BBB, these hits present novel starting points for optimization as future treatments for pFLA-caused diseases.

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“…We also identified the EGFR inhibitor ASP-8273 (naquotinib) [21][22][23] as an inhibitor of T. cruzi with good potency (EC 50 of 2.7 nM) and a SI of 191. Several studies have successfully explored kinase inhibitors of trypanosomatids as therapeutic agents [24][25][26], and this compound may represent yet another possible candidate for repurposing or further chemical derivatization.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi

et al. 2020

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Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened 7680 compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified seven compounds of interest with potent in vitro activity against the parasite with a therapeutic index of 10 or greater, including the previously unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of new T. cruzi leads that can potentially move quickly to the clinic.

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Hit-to-Lead Optimization of Benzoxazepinoindazoles As Human African Trypanosomiasis Therapeutics

Cited by 15 publications

References 7 publications

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi

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